Process for preparing optically active 2,3-dihydrobenzofuran compounds

ABSTRACT

A process for preparing optically active 2,3-dihydrobenzofuran compounds which comprises subjecting a 2,3-dihydrobenzofuran compound represented by the general formula or a salt thereof to optical resolution with an optically active acid compound:  
                 
 
[wherein R 1  and R 2  are each hydrogen or an optionally substituted hydrocarbon group; R 3  is an optionally substituted aromatic group; and C is a benzene ring which may further have a substituent in addition to the amino group]. The process enables industrially advantageous production of intermediates for the synthesis of optically active 2,3-dihydrobenzofuran compounds useful as preventive and/or therapeutic drugs for neurodegenerative diseases and so on.

TECHNICAL FIELD

The present invention provides an industrially advantageous productionmethod for synthetic intermediates of optically active2,3-dihydrobenzofuran derivatives that are useful as medicine forpreventing or treating nerve degenerative disease and the like.

BACKGROUND ART

As a benzofuran derivative useful for the prevention or treatment ofnerve degenerative diseases and the like and a production methodthereof, WO00/34262 discloses, for example, a production method for(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-aminecomprising optical resolution of2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineby HPLC using a column for optical isomer separation.

The development for a convenient and industrially advantageousproduction method of a compound having antioxidant action itself, whichis useful as medicine as well as a synthetic intermediate for anoptically active 2,3-dihydrobenzofuran derivative useful as a medicinefor preventing or treating nerve degenerative diseases and the like,have been desired.

SUMMARY OF THE INVENTION

The present inventors have conducted intensive studies on a method foroptical resolution of the 2,3-dihydrobenzofuran compound or a saltthereof represented by the formula (I) mentioned below, and found thatan optically active substance represented by the formula (I) or a saltthereof can be obtained in high yield and high purity, by forming adiastereomeric salt with an optically active acidic compound and thenseparating the compound. Based on this finding, the present inventionhas been completed.

Namely, the present invention provides

(1) a process for producing an optically active 2,3-dihydrobenzofurancompound or a salt thereof, comprising optically resolving a2,3-dihydrobenzofuran compound represented by the formula:

wherein R¹ and R² are each a hydrogen atom or an optionally substitutedhydrocarbon group, R³ is an optionally substituted aromatic group, ringC is a benzene ring optionally having a substituent besides the aminogroup or a salt thereof, with an optically active acidic compound;

(2) the process according to the above-mentioned (1), wherein R¹ and R²are each a C₁₋₆ alkyl group;

(3) the process according to the above-mentioned (1), wherein R³ is aphenyl group optionally having C₁₋₆ alkyl and/or halogen atom;

(4) the process according to the above-mentioned (1), wherein the ring Cis a benzene ring fully substituted with the substituents selected froma C₁₋₆ alkyl, a C₁₋₆ alkoxy and a C₁₋₃ alkylenedioxy besides the aminogroup;

(5) the process according to the above-mentioned (1), wherein thecompound represented by the formula (I) or a salt thereof is a compoundrepresented by the formula:

wherein R^(1′) and R^(2′) are each a C₁₋₆ alkyl group, R^(3′) is aphenyl group optionally having C₁₋₆ alkyl and/or halogen atom, R⁴, R⁵and R⁶ are each a C₁₋₆ alkyl, a C₁₋₆alkoxy or a C₁₋₃alkylenedioxy, or asalt thereof;

(6) the process according to the above-mentioned (1), wherein theoptically active acidic compound is an optically activeO,O′-diacyltartaric acid derivative;

(7) the process according to the above-mentioned (1), wherein theoptically active acidic compound is an optically active N-acylamino acidderivative;

(8) the process according to the above-mentioned (1), wherein theoptically active acidic compound is an optically active phosphoric acidderivative represented by the formula:

wherein Ar is an optionally substituted aromatic hydrocarbon group,R^(1a) and R^(2a) are each a hydrogen atom, an optionally substitutedlower alkyl group, an optionally substituted lower alkoxy group, ahalogen atom or a nitro group, or R^(1a) and R^(2a) may be together toform an optionally substituted alkylene group or an optionallysubstituted methylenedioxy, and the symbol * shows the position of anasymmetric carbon;

(9) the process according to the above-mentioned (1), wherein theoptically active acidic compound is an optically activeO,O′-di-(p-toluoyl)tartaric acid;

(10) the process according to the above-mentioned (1), wherein theoptically active acidic compound is an optically activeN-(3,5-dinitrobenzoyl)-α-phenylglycine;

(11) the process according to the above-mentioned (8), wherein thephosphoric acid derivative represented by the formula (II) is anoptically active compound of2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide;

(12) the process according to the above-mentioned (5), wherein R⁴, R⁵and R⁶ are each a methyl group;

(13) a salt of a compound represented by the formula (I′) with anoptically active O,O′-di-(p-toluoyl)tartaric acid, an optically activeN-(3,5-dinitrobenzoyl)-α-phenylglycine or an optically active2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide;

(14) a salt of(R)-(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-aminewith (2S,3S)-O,O′-di-(p-toluoyl)tartaric acid;

(15) a salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine with(2S,3S)-O,O′-di-(p-toluoyl)tartaric acid;

(16) a salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine with(S)-N-(3,5-dinitrobenzoyl)-α-phenylglycine;

(17) a salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine with(+)-2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane2-oxide;

(18) a salt of(+)-2,2,4,6,7-pentamethyl-3-(4-bromophenyl)-2,3-dihydro-1-benzofuran-5-aminewith (2S,3S)-O,O′-di-(p-toluoyl)tartaric acid;

(19) a process for preparing a compound represented by the formula:

wherein R¹ and R² are each a hydrogen atom or an optionally substitutedhydrocarbon group, R³ is an optionally substituted aromatic group, ringA is an optionally substituted benzene ring, ring B is a 5- to7-membered nitrogen-containing heterocyclic ring optionally substitutedwith a halogen or an optionally substituted hydrocarbon group, ring C isa benzene ring optionally having substituent besides the amino group, ora salt thereof, comprising optically resolving a 2,3-dihydrobenzofurancompound represented by the formula:

wherein the symbols are as defined above, or a salt thereof with anoptically active acidic compound to give a compound represented by theformula:

wherein the symbols are as defined above, or a salt thereof, andreacting the obtained compound (I″) with a compound represented by theformula:

wherein L¹ and L² are each a leaving group and the ring A is as definedabove, or a salt thereof, optionally in the presence of a base;

(20) the process according to the above-mentioned (19), wherein the ringB is a 5-membered nitrogen-containing heterocyclic ring; and

(21) the process according to the above-mentioned (19), wherein(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline(also referred to as(R)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-benzofuran-5-yl]-2,3-dihydro-1H-isoindole,and so forth),(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(1-methylethylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindolineor(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-bromophenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,or a salt thereof is produced.

According to the present invention, the resolution of optical isomers atthe 3-position apart from the amino group substituted at the 5-positionof the benzofuran ring, become possible by using the present opticallyactive acidic compound.

DETAILED DESCRIPTION OF THE INVENTION

In the above-mentioned formula, R¹ and R² are each a hydrogen atom or anoptionally substituted hydrocarbon group.

The “hydrocarbon group” of the “optionally substituted hydrocarbongroup” represented by R¹ or R² includes for example a chain or cyclichydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl andthe like) and the like. Of these, a chain or cyclic hydrocarbon grouphaving 1 to 16 carbon atoms and the like are preferred.

As the “alkyl”, for example, a C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike) and the like are preferred.

As the “alkenyl”, for example, a C₂₋₆ alkenyl (e.g., vinyl, allyl,isopropenyl, butenyl, isobutenyl, sec-butenyl and the like) and the likeare preferred.

As the “alkynyl”, for example, a C₂₋₆ alkynyl (e.g., ethynyl, propargyl,butynyl, 1-hexynyl and the like) and the like are preferred.

As the “cycloalkyl”, for example, a C₃₋₆ cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like) and the like arepreferred.

As the “aryl”, for example, a C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl,2-naphthyl, biphenylyl, 2-anthryl and the like) and the like arepreferred.

The “substituent” of the “optionally substituted hydrocarbon group”represented by R¹ or R² includes for example (1) a halogen atom (e.g.,fluorine, chlorine, bromine, iodine and the like), (2) a C₁₋₃alkylenedioxy (e.g., methylenedioxy, ethylenedioxy and the like), (3) anitro, (4) a cyano, (5) an optionally halogenated C₁₋₆ alkyl, (6) anoptionally halogenated C₂₋₆ alkenyl, (7) an optionally halogenated C₂₋₆alkynyl, (8) an optionally halogenated C₃₋₆ cycloalkyl, (9) a C₆₋₁₄ aryl(e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and thelike), (10) an optionally halogenated C₁₋₆ alkoxy, (11) an optionallyhalogenated C₁₋₆ alkylthio or mercapto, (12) a hydroxy, (13) an amino,(14) a mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino and thelike), (15) a mono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino and the like), (16) a di-C₁₋₆ alkylamino (e.g.,dimethylamino, diethylamino and the like), (17) a di-C₆₋₁₄ arylamino(e.g., diphenylamino and the like), (18) an acyl, (19) an acylamino,(20) an acyloxy, (21) a 5- to 7-membered saturated cyclic aminooptionally having substituent, (22) a 5- to 10-membered aromaticheterocyclic group (e.g., 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-,4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl and the like), (23)a sulfo, (24) a C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy and thelike), and the like.

The “hydrocarbon group” may have, for example, 1 to 5, preferably 1 to 3of the above-mentioned substituents at the substitutable position, andwhen the number of the substituents is two or more, the substituents maybe the same or different.

The above-mentioned “optionally halogenated C₁₋₆ alkyl” includes forexample a C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) optionallyhaving 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like) and the like. Specific examplesinclude methyl, chloromethyl, difluoromethyl, trichloromethyl,trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyland the like.

The above-mentioned “optionally halogenated C₂₋₆ alkenyl” includes forexample a C₂₋₆ alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl,isobutenyl, sec-butenyl and the like) optionally having 1 to 5,preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like) and the like. Specific examples include vinyl,allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl,3,3,3-trifluoro-1-propenyl, 4,4,4-trifluoro-1-butenyl and the like.

The above-mentioned “optionally halogenated C₂₋₆ alkynyl” includes forexample a C₂₋₆ alkynyl (e.g., ethynyl, propargyl, butynyl, 1-hexynyl andthe like) optionally having 1 to 5, preferably 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like) and the like.Specific examples include ethynyl, propargyl, butynyl, 1-hexynyl,3,3,3-trifluoro-1-propynyl, 4,4,4-trifluoro-1-butynyl and the like.

The above-mentioned “optionally halogenated C₃₋₆cycloalkyl” includes forexample a C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like) optionally having 1 to 5, preferably 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like)and the like. Specific examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like.

The above-mentioned “optionally halogenated C₁₋₆alkoxy” includes forexample a C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like)optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like) and the like. Specificexamples include for example methoxy, difluoromethoxy, trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy andthe like.

The above-mentioned “optionally halogenated C₁₋₆ alkylthio” includes forexample a C₁₋₆alkylthio (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like)optionally having 1 to 5, preferably 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like) and the like. Specificexamples include methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.

The above-mentioned “acyl” includes for example formyl, carboxy,carbamoyl, a C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl and the like),a C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl and the like), a C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl and the like), a C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl and the like), a C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, phenylpropionyl and the like), a C₆₋₁₄ aryloxy-carbonyl(e.g., phenoxycarbonyl and the like), a C₇₋₁₆aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl and the like), a 5- or6-membered heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl,2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl,thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl andthe like), a mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl and the like), a di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like),a C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl and the like), a thiocarbamoyl, a 5- or 6-memberedheterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and thelike), a C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and thelike), a C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl and the like), a C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl and the like), a C₆₋₁₄ arylsulfinyl (e.g.,phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like) andthe like.

The above-mentioned “acylamino” includes for example a formylamino, aC₁₋₆ alkyl-carbonylamino (e.g., acetylamino and the like), aC₆₋₁₄aryl-carbonylamino (e.g., phenylcarbonylamino,naphthylcarbonylamino and the like), a C₁₋₆ alkoxy-carbonylamino (e.g.,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino and the like), a C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino and the like), a C₆₋₁₄arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino and the like) and the like.

The above-mentioned “acyloxy” includes for example a C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy and the like), a C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy and the like), aC₁₋₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy and the like), a mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy and thelike), a di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy and the like), a C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy and the like), a nicotinoyloxyand the like.

The “5- to 7-membered saturated cyclic amino” of the above-mentioned “5-to 7-membered saturated cyclic amino optionally having substituent”includes for example morpholino, thiomorpholino, piperazin-1-yl,piperidino, pyrrolidin-1-yl and the like. The “substituent” of the “5-to 7-membered saturated cyclic amino optionally having substituent”includes 1 to 3 substituents such as a C₁₋₆ alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyland the like), a C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl,biphenylyl, 2-anthryl and the like), a 5- to 10-membered aromaticheterocyclic group (e.g., 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-,4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl and the like) andthe like.

Preferably, R¹ and R² are a C₁₋₆ alkyl group such as methyl and thelike.

R³ is an optionally substituted aromatic group.

The “aromatic group” includes aromatic hydrocarbon group, aromaticheterocyclic group and the like.

The “aromatic hydrocarbon group” includes for example a monocyclic orfused polycyclic (bicyclic or tricyclic) aromatic hydrocarbon grouphaving 6 to 14 carbon atoms and the like. Specific examples thereofinclude a C₆₋₁₄ aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl,anthryl and the like, preferably a C₆₋₁₀ aryl such as phenyl,1-naphthyl, 2-naphthyl and the like.

The “aromatic heterocyclic group” includes for example a 5- to14-membered, preferably 5- to 10-membered aromatic heterocyclic groupcontaining one or more (e.g., 1 to 4) heteroatoms selected from anitrogen atom, a sulfur atom and an oxygen atom besides carbon atoms.Specific examples thereof include for example an aromatic heterocyclicring such as thiophene, benzothiophene, benzofuran, benzimidazole,benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene,furan, isoindolidine, xanthrene, phenoxathiine, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole,1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole,isothiazole, phenothiazine, oxazole, isoxazole, furazane, phenoxazineand the like, or a monovalent group formed by removing any hydrogen atomfrom a ring formed by condensation of the above-mentioned ring(preferably monocyclic ring) with one or more (preferably 1 or 2) ofaromatic rings (e.g., benzene ring and the like) and the like.

As the “substituent” of the “optionally substituted aromatic group”, thesubstituents and the number thereof are exemplified by those for the“optionally substituted hydrocarbon group” represented by R¹ or R²mentioned above.

R³ is preferably a phenyl group optionally having 1 to 3 of C₁₋₆ alkyland/or halogen atom, and more preferably a phenyl group optionallyhaving C₁₋₆ alkyl or halogen atom at the para position. The “C₁₋₆ alkyl”of “a phenyl group optionally having C₁₋₆ alkyl and/or halogen atom”includes, as mentioned above, for example methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike, and the “halogen atom” includes for example fluorine, chlorine,bromine, iodine and the like.

The ring C optionally has 1 to 3 (preferably 3) substituents at thesubstitutable position besides the amino group, and when the number ofthe substituent is two or more, the substituents may be the same ordifferent.

As the “substituent” that the ring C may further have, the substituentsand the number thereof are exemplified by those for the “substituents”of the “optionally substituted hydrocarbon group” represented by theabove-mentioned R¹ or R².

The ring C is preferably a benzene ring fully substituted withsubstituents selected from a C₁₋₆ alkyl, a C₁₋₆alkoxy and a C₁₋₃alkylenedioxy besides the amino group. Specifically, a benzene ringhaving three C₁₋₆ alkyls such as methyl and the like is preferred.

In the above-mentioned formula, the “C₁₋₆ alkyl group” represented byR^(1′), R^(2′), R^(3′), R^(4′), R^(5′) or R^(6′) and “C₁₋₆ alkoxy group”represented by R⁴, R⁵ or R⁶ include groups similar to those exemplifiedfor the above-mentioned R¹, R² and R³.

The “C₁₋₃ alkylenedioxy” represented by R⁴, R⁵ and R⁶ include forexample methylenedioxy, ethylenedioxy and the like.

Preferably, R⁴, R⁵ and R⁶ are a C₁₋₆ alkyl group such as methyl and thelike.

The salt of the compound represented by the formula (I) and (I′)includes for example a salt with an inorganic acid, a salt with anorganic acid, a salt with an amino acid and the like. Preferred examplesof the salt with an inorganic acid includes for example a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid orphosphoric acid or the like. Preferred examples of the salt with anorganic acid includes for example a salt with formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid or p-toluenesulfonic acid or the like. Preferredexamples of the salt with an amino acid include for example a salt withaspartic acid, glutamic acid, glycine or alanine or the like.

In the production method of the present invention, an optically activeform of the compound represented by the above-mentioned formula (I) or asalt thereof [hereinafter sometimes referred to as an optically activeform of a compound (I)] can be produced by converting the2,3-dihydrobenzofuran compound or a salt thereof represented by theformula (I) [hereinafter sometimes referred to as a compound (I)] into asalt with an optically active acidic compound and subjecting the salt tooptical resolution.

The optical resolution of the optical isomer mixture (I) of the2,3-dihydrobenzofuran derivative with an optically active acidiccompound can be carried out, for example, according to the followingoperations.

Firstly, the (I) and an optically active acidic compound which is anacidic resolution agent, are reacted in a suitable solution to form adiastereomeric salt.

The optically active acidic compound includes, for example, an opticallyactive tartaric acid derivative such as an optically activeO,O′-di-acyltartaric acid derivative, for example, an optically activeamino acid derivative such as an optically active N-acylamino acid, andfor example, an optically active phosphoric acid derivative such as acompound represented by the formula (II), and the like. The preferredacyl group for the O,O′-di-acyltartaric acid derivative include a lower(C₁₋₆) alkanoyl group such as acetyl, propionyl, butyryl, valeryl andthe like, and an aroyl group such as benzoyl, p-chlorobenzoyl, naphthoyland the like. The most preferable O,O′-di-acyltartaric acid isO,O′-di-(p-toluoyl)tartaric acid.

The preferable N-acyl group for the N-acylamino acid derivative includesa lower (C₁₋₆) alkanoyl group such as acetyl, propionyl, butyryl,valeryl and the like, an aroyl group such as benzoyl, p-chlorobenzoyl,naphthoyl and the like. The amino acid includes for exampleα-phenylglycine. The most preferable N-acylamino acid derivative isN-(3,5-dinitrobenzoyl)-α-phenylglycine.

The optically active phosphoric acid derivative represented by theformula (II) can be obtained easily according to the methods disclosedin JP-A S61-103886, J. Org. Chem., 50, 4508 (1985) and the like, andsome compounds are readily available as commercial products.Specifically, for example,2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide,4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane2-oxide,4-(2,4-dichlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane2-oxide,2-hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinane2-oxide,2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane-2-oxideand the like are exemplified.

The “aromatic hydrocarbon group” of the “optionally substituted aromatichydrocarbon group” represented by Ar includes a C₆₋₁₄ aryl (e.g.,phenyl, naphthyl and the like) and the like. The “substituent” of the“optionally substituted aromatic hydrocarbon group” includes the samenumber and the same substituents as those exemplified for the“substituent” of the above-mentioned “optionally substituted hydrocarbongroup” represented by R¹ or R². The “substituent” preferably includes 1to 2 substituents selected from a C₁₋₆ alkyl group such as methyl, ethyland the like, a C₁₋₆ alkoxy group such as methoxy, ethoxy and the like,a halogen atom such as fluorine, chlorine, bromine and the like.

The “lower alkyl group” of the “optionally substituted lower alkylgroup” represented by R^(1a) and R^(2a) includes for example a C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like) and the like. The“substituent” of the “optionally substituted lower alkyl group” includesthe same number and the same substituents as those exemplified for the“substituent” of the above-mentioned “optionally substituted hydrocarbongroup” represented by R¹ or R². The “substituent” preferably includes 1to 2 substituents selected from a halogen atom (e.g., fluorine,chlorine, bromine and the like), nitro, cyano, a C₁₋₄ alkanoyl (e.g.,acetyl, propionyl and the like), a carboxyl, a C₁₋₄ alkoxy (e.g.,methoxy, ethoxy, propoxy and the like), a C₁₋₄ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl and the like), acarbamoyl, a C₁₋₄alkoxy-carbonylamino (e.g., methoxycarbonylamino,ethoxycarbonylamino and the like) and the like.

The “lower alkoxy group” of the “optionally substituted lower alkoxygroup” represented by R^(1a) and R^(2a) includes for example a C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy and the like) and the like. The“substituent” of the “optionally substituted lower alkoxy group”includes the same number and the same substituents as those exemplifiedfor the “substituent” of the above-mentioned “optionally substitutedhydrocarbon group” represented by R¹ or R². The “substituent” preferablyincludes 1 to 2 substituents selected from a C₁₋₄ alkanoyl (e.g.,acetyl, propionyl and the like), carboxyl, hydroxy group, a C₁₋₄ alkoxy(e.g., methoxy, ethoxy, propoxy and the like), a C₁₋₄ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl and the like) andthe like.

The “halogen atom” represented by R^(1a) and R^(2a) includes fluorine,chlorine, bromine, iodine and the like.

When the R^(1a) and R^(2a) are together to represent an optionallysubstituted alkylene group, the optionally substituted alkylene groupincludes an unsubstituted alkylene having 2 to 6 carbons (dimethylene,trimethylene, tetramethylene, pentamethylene) and a group having 1 or 2substituents selected from lower alkyl group (e.g., a C₁₋₄ alkyl such asmethyl, ethyl, propyl and the like), lower alkoxy group (e.g., a C₁₋₄alkoxy such as methoxy, ethoxy, propoxy and the like), nitro group, ahalogen atom (e.g., fluorine, chlorine, bromine, iodine) and the like atany position of these alkylene.

When the R^(1a) and R^(2a) are together to represent an optionallysubstituted methylenedioxy group, the methylene group thereof may besubstituted with, for example a halogen atom (e.g., fluorine, chlorine,bromine, iodine), a nitro group and the like.

The preferable examples of R^(1a) and R^(2a) include the case in whichboth R^(1a) and R^(2a) are methyl group, and the case in which both arebound together to represent a tetramethylene group.

Of the optically active phosphoric acid derivatives represented by theformula (II),2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxideis most preferred.

The amount of the acidic resolution agent to be used is 0.1 to 4-foldmol, preferably 0.6 to 2.5-fold mol relative to the (I). In addition, onthis occasion, a mineral acid such as hydrochloric acid, sulfuric acid,phosphoric acid and the like or an organic acid such as acetic acid,propionic acid, fumaric acid, maleic acid and the like may be co-existedwith the resolution agent in a such a way that the amount of acidsincluding resolution agent are in the above-mentioned mol range.

The solvent to be used is preferably a solvent which does not chemicallychange the (I) and the acidic resolution agent and hardly dissolves oneof the diastereomeric salts formed. For example, water, alcohols such asmethanol, ethanol, isopropanol and the like, ethers such asdiethylether, diisopropylether, 1,2-dimethoxyethane, tetrahydrofuran,tetrahydropyran and the like, ketones such as acetone, 2-butanone andthe like, nitrites such as acetonitrile and the like, aromatichydrocarbons such as benzene, toluene, are exemplified. One of thesesolvents can be used solely, or two or more of them can be used as amixture. The amount of the solvent to be used is generally 1 to1000-fold amounts, preferably 1 to 100-fold amounts relative to the (I).The temperature is generally not less than 15° C., and may be in therange not more than the boiling point of the solvent to be used.

After the formation of the diastereomeric salts, one of the salts can becrystallized out by cooling or concentration. In a certain condition, ahardly-soluble salt is readily crystallized out by leaving or stirringunder the room temperature, without operation such as cooling orconcentration.

The crystallized salt can be readily separated by a general solid-liquidseparation method such as filtration, centrifugation and the like.Furthermore, the purity of the separated salt crystals can be enhancedby a method known per se such as recrystallization and the like, ifnecessary.

After the separation of the hardly-soluble salt, the mother liquor as itis sometimes contains only an readily-soluble salt. The readily-solublesalt can be separated as it is, or by concentration and the subsequentcooling.

Of the obtained salts, a salt of a compound represented by the formula(I′) with an optically active O,O′-di-(p-toluoyl)tartaric acid, anoptically active N-(3,5-dinitrobenzoyl)-α-phenylglycine or an opticallyactive form of2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide,and specifically

-   a salt of    (R)-(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine    with (2S,3S)-O,O′-di-(p-toluoyl)tartaric acid,-   a salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)    phenyl]-2,3-dihydro-1-benzofuran-5-amine with    (2S,3S)-O,O′-di-(p-toluoyl)tartaric acid,-   a salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)    phenyl]-2,3-dihydro-1-benzofuran-5-amine with    (S)-N-(3,5-dinitrobenzoyl)-α-phenylglycine,-   a salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)    phenyl]-2,3-dihydro-1-benzofuran-5-amine with    (+)-2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane    2-oxide, and-   a salt of    (+)-2,2,4,6,7-pentamethyl-3-(4-bromophenyl)-2,3-dihydro-1-benzofuran-5-amine    with (2S,3S)-O,O′-di-(p-toluoyl)tartaric acid, are novel salts.

For the decomposition of the thus-obtained salt, any known methods maybe used. For example, the object can be achieved by the treatment withan alkaline or an acid in a aqueous solution. The free optically active2,3-dihydrobenzofuran compound can be isolated by treating the salt withaqueous base such as an aqueous solution of sodium hydroxide, sodiumhydrogencarbonate and the like, and successively separating bysolid-liquid separation method such as filtration, centrifugation andthe like or extracting with an organic solvent and the like. Thetreatment with a base is generally carried out at about −10 to 25° C.,and the amount of the base to be used is 1 to 5-fold mol relative to thediastereomeric salts. The concentration of such base is 1 to 50 wt %,preferably 5 to 20 wt %.

The basic water layer after the separation of the optically active2,3-dihydrobenzofuran compound may be made acidic with an acid such ashydrochloric acid, sulfuric acid and the like to recover the resolutionagent, and the recovered agent can be reused.

The thus-obtained optically active 2,3-dihydrobenzofuran compound can beused as a reaction solution as it is, or can be used in the nextreaction as a crude substance, or can be used after purification by ageneral separation mean (e.g., recrystallization, distillation,chromatography and the like).

As mentioned above, according to the production method of the presentinvention, the resolution of optical isomers at the 3-position apartfrom the amino group substituted at the 5-position of the benzofuranring becomes possible, using the optically active acidic compound.

In the above-mentioned production method, while the compound(I) used asa starting material can be produced by a method disclosed in WO00/34262or a similar method thereto, it can be produced by the following method.

wherein R⁷ is a hydrogen atom or a group formed by removing onemethylene group from R¹, and the other symbols are as defined above.

The compound (VI) can be produced by Claisen rearrangement of thecompound (V). This reaction is advantageously carried out under thepresence of a base catalyst without solvent or in a solvent inert to thereaction. As the base catalyst, for example, carbonate alkaline metalsalts such as sodium hydrogencarbonate, potassium hydrogencarbonate,sodium carbonate, potassium carbonate, cesium carbonate and the like,amines such as triethylamine, N-ethyldiisopropylamine, DBU(1,8-diazabicyclo[5.4.0]-7-undecene), DBN(1,5-diazabicyclo[4.3.0]-5-nonene) and the like, are preferably used.The amount of the base catalyst to be used is 0.01 mol % to 5 mol %,preferably 0.1 mol % to 3 mol % relative to 1 mol of the compound (V).As the solvent, which is not specifically limited as long as thereaction proceeds, for example, alcohols such as methanol, ethanol,propanol and the like, hydrocarbons such as cyclohexane, hexane,benzene, toluene, xylene, mesitylene and the like, ethers such astetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethylether,diisopropylether and the like, anilines such as N,N-dimethylaniline,N,N-diethylaniline and the like, halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like, or a mixed solvent thereof, are used.

The reaction period is generally about 30 min to 24 hr, preferably 1 hrto 12 hr. The reaction temperature is generally 50° C. to 350° C.,preferably 150° C. to 220° C.

The compound (VII) is produced by ring-closure of the compound (VI) inthe presence of an acid.

As the acid, mineral acids such as hydrochloric acid, hydrobromic acid,sulfuric acid and the like, sulfonic acids such as p-toluenesulfonicacid, camphorsulfonic acid and the like, Lewis acids such as aluminumchloride, boron trifluoride and the like are used.

The amount of the acid to be used is generally 1 to 500 mol, preferably5 to 200 mol relative to 1 mol of the compound (VI).

In this reaction, while the acid to be used may be also used as asolvent, it is advantageous to use an inert solvent to this reaction.Such solvent is not specifically limited as long as the reactionproceeds, and for example, alcohols such as methanol, ethanol, propanol,butanol, isobutanol, methoxyethanol and the like, hydrocarbons such ascyclohexane, hexane, benzene, toluene, xylene, mesitylene and the like,ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane,diethylether, diisopropylether and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramideand the like, sulfoxides such as dimethylsulfoxide and the like,halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane and the like, or a mixed solventthereof, are used.

The reaction period is generally about 30 min to 24 hr, preferably 1 hrto 12 hr. The reaction temperature is generally 0° C. to 200° C.,preferably 10° C. to 180° C.

The compound represented by the formula:

wherein the symbols in the formula are as defined above, or a saltthereof (hereinafter sometimes referred to as a compound (I″)), which isone of the enantiomers of the optically active 2,3-dihydrobenzofurancompound obtained by the production method of the present invention, isuseful as a medicine itself, and is also useful as a synthetic startingmaterial or synthetic intermediate for the production of an opticallyactive medicine. For example, according to the method disclosed inWO00/34262, a compound represented by the formula:

wherein ring A is an optionally substituted benzene ring, ring B is 5-to 7-membered nitrogen-containing heterocyclic ring optionallysubstituted with a halogen or an optionally substituted hydrocarbongroup, and the other symbols are as defined above or a salt thereof(hereinafter sometimes referred to as a compound (IV)), which isobtained by reacting the compound (I″) obtained by the production methodof the present invention and a compound represented by the formula:

wherein ring A is as defined above, and L¹ and L² are each a leavinggroup or a salt thereof (hereinafter sometimes referred to as a compound(III)) optionally in the presence of a base, has superior medicalactions such as neurotrophic factor-like action, neurotrophic factoractivity-enhancing action, nerve degeneration-suppressing action, nerveregeneration-accelerating action, antioxidant action or a suppressingaction for nerve cell death due to β amyloid and the like, and also hassuperior characteristics such as low toxicity, decreased side effect andthe like, and is useful as a pharmaceutical agent.

In the compounds (III) and (IV), as the substituents of the “optionallysubstituted benzene ring” represented by the ring A, ring A may have 1to 4 (preferably 1 or 2) substituents exemplified by the “substituent”for the “optionally substituted hydrocarbon group” represented by theabove-mentioned R¹ or R² at the substitutable position of the ring, andwhen the number of the substituent is two or more, the substituent maybe the same or different.

In the compound (IV), the “5- to 7-membered nitrogen-containingheterocyclic ring” represented by the ring B includes a 5- to 7-memberednitrogen-containing heterocyclic ring such as pyrrole (e.g., 1H-pyrroleand the like), dihydropyrrole (e.g., 2,5-dihydro-1H-pyrrole and thelike), dihydropyridine (e.g., 1,2-dihydropyridine and the like),tetrahydropyridine (e.g., 1,2,3,4-tetrahydropyridine and the like),azepine (e.g., 1H-azepine and the like), dihydroazepine (e.g.,2,3-dihydro-1H-azepine, 2,5-dihydro-1H-azepine, 2,7-dihydro-1H-azepineand the like), tetrahydroazepine (e.g., 2,3,6,7-tetrahydro-1H-azepine,2,3,4,7-tetrahydro-1H-azepine and the like) and the like.

The “halogen” as the “substituents” that the ring B may have includesfor example fluorine, chlorine, bromine, iodine and the like.

The “optionally substituted hydrocarbon group” as the substituent thatthe ring B may have includes those exemplified by the “optionallysubstituted hydrocarbon group” represented by the above-mentioned R¹ orR².

The ring B may have 1 to 3 of these substituents at the substitutableposition, and when the number of the substituent is two or more, thesubstituent may be the same or different.

More specifically, the group represented by the formula:

wherein the symbols are as defined above, includes groups represented bythe formulas:

wherein R⁸ and R⁹ are the same or different and each is a hydrogen atom,a halogen or an optionally substituted hydrocarbon group, and the ring Ais as defined above, and the like, preferably the groups represented bythe formulas:

wherein the symbols are as defined above, and the like, and morepreferably the groups represented by the formulas:

wherein the symbols are as defined above, and the like. Of these, thegroups represented by the formula:

wherein the symbols are as defined above, and the like are specificallypreferred.

The “halogen” or “optionally substituted hydrocarbon group” representedby R⁸ and R⁹ includes those exemplified by the “halogen” or “optionallysubstituted hydrocarbon group” as the “substituent” of theabove-mentioned ring B.

The “leaving group” represented by L¹ and L² includes for example ahydroxy, a halogen atom (e.g., fluorine, chlorine, bromine, iodine andthe like), an optionally halogenated C₁₋₅ alkylsulfonyloxy (e.g.,methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy andthe like), an optionally substituted C₆₋₁₀ arylsulfonyloxy and the like.The “optionally substituted C₆₋₁₀ arylsulfonyloxy” includes aC₆₋₁₀arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy andthe like) optionally having 1 to 3 substituents selected from a C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like), a C₁₋₆alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy and the like) and a nitro. Specific examples thereofinclude benzenesulfonyloxy, m-nitrobenzenesulfonyloxy,p-toluenesulfonyloxy and the like.

The compound (III) is a compound which may form the ring represented byA and B of the compound (IV) together with the nitrogen atom of theamino group substituted on the ring C of the compound (I″).

The amount of the compound (III) to be used is about 0.8 to about 5.0mol, preferably about 1.0 to about 2.0 mol relative to 1 mol of thecompound (I″).

The “base” includes basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogencarbonate and the like,aromatic amines such as pyridine, lutidine and the like, tertiallyamines such as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methyl morpholine and thelike, alkaline metal hydrides such as sodium hydride, potassium hydrideand the like, metal amides such as sodium amide, lithiumdiisopropylamide, lithium hexamethyl disilazide and the like, metalalkoxides such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like.

The amount of the base to be used is about 0.5 to about 10.0 mol,preferably about 1.0 to about 3.0 mol relative to 1 mol of the compound(I″). Furthermore, if necessary, the production can be carried out byreacting with the base under the co-existence of a quaternary ammoniumsalt.

The “quaternary ammonium salt” includes for example tetrabutylammoniumiodide and the like.

The amount of the quaternary ammonium salt to be used is about 0.1 toabout 3.0 mol, preferably about 0.5 to about 1.0 mol relative to 1 molof the compound (I″).

It is advantageous to carry out the present reaction using an inertsolvent. Such solvent is not specifically limited as long as thereaction exceeds, and includes, for example, alcohols such as methanol,ethanol, propanol, butanol and the like, ethers such as diethylether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like, hydrocarbonssuch as benzene, toluene, cyclohexane, hexane and the like, amides suchas N,N-dimethylformamide, N,N-dimethylacetamide and the like,halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane and the like, nitrites such asacetonitrile, propionitrile and the like, sulfoxides such asdimethylsulfoxide and the like, or a mixed solvent thereof and the like,are preferred.

The reaction period is generally about 30 min to about 72 hr, preferablyabout 3 hr to about 24 hr. The reaction temperature is generally about−20 to about 200° C., preferably about 20 to about 150° C.

Examples of the compound (IV) include(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(1-methylethylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-bromophenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindolineor a salt thereof.

The salt of the compound (IV) may be, when the compound (IV) has anacidic group such as —COOH and the like, for example, a metal salt, anammonium salt, a salt with an organic base and the like, or when thecompound (IV) has a basic group such as —NH₂ and the like, for example,a salt with an inorganic acid, an organic acid, or a basic or acidicamino acid or the like, or an intramolecular salt. Preferred examples ofthe metal salt include for example alkaline metal salts such as sodiumsalt, potassium salt and the like; alkaline earth metal salts such ascalcium salt, magnesium salt, barium salt and the like; aluminum saltand the like. Preferred examples of the salt with an organic baseinclude for example a salt with trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine, N,N-dibenzylethylenediamine or the like. Preferredexamples of the salt with an inorganic acid include for example a saltwith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid or the like. Preferred examples of the salt with anorganic acid include for example a salt with formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid or the like. Preferredexamples of the salt with a basic amino acid includes for example a saltwith arginine, lysine, ornithine or the like, and preferred examples ofthe salt with an acidic amino acid includes for example a salt withaspartic acid, glutamic acid or the like.

Of these, a pharmaceutically acceptable salt is preferred. For example,when the compound has an acidic functional group, inorganic salts suchas alkaline metal salts (e.g., a sodium salt, a potassium salt and thelike), alkaline earth metal salts (e.g., a calcium salt, a magnesiumsalt, a barium salt and the like) and the like, ammonium salts and thelike are exemplified. Alternatively, when the compound has a basicfunctional group, inorganic salts such as hydrochloride, sulfate,phosphate, hydrobromide and the like, and organic salts such as acetate,maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate,citrate, tartarate and the like, are exemplified.

The compound (IV) acts as a neurotrophic factor-like substance, aneurotrophic factor activity-enhancing substance or a nervedegeneration-suppressing substance, or a β amyloid toxicity-suppressingsubstance and the like, to mammals (e.g., mouse, rat, hamster, rabbit,cat, dog, cattle, sheep, monkey, human and the like), and suppressesnerve cell death and accelerates nerve regeneration. Furthermore, thecompound of the present invention has activation action for cholinergicsystem (e.g., activity-enhancing action for cholineacetyltransferase andthe like), and increases the content of acetylcholine and activatesnerve function and the like.

Therefore, the compound (IV) is useful for, for example, nervedegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis (ALS), Huntington's disease,spinocerebellar degeneration and the like), psychoneurosis (e.g.,schizophrenia and the like), head trauma, spinal injury, cerebrovasculardisorder, cerebrovascular dementia, peripheral nerve disorder (e.g.,diabetic nerve disorder and the like) and the like. The compound (IV) isused for an agent for prevention or treatment of these diseases.

The usage such as preparation for prevention or treatment of thesediseases, administration route, dosage form and the like, can followthose disclosed in WO00/34262.

Namely, the compound (IV) has low toxicity, and can be safelyadministered orally or parenterally (e.g., local, rectal, intravenousand the like) as it is, or as a pharmaceutical composition such astablet (including sugar-coated tablet, film-coated tablet, buccaldisintegrating tablet and the like), powder, granule, capsule (includingsoft capsule), liquid, injection, suppository, sustained-release agent,adhesive and the like, which is produced by mixing with apharmacologically acceptable carrier according to a mean known per se.

The content of the compound (IV) in the preparation of the presentinvention is about 0.01 to about 100 wt % relative to whole preparation.

The dose varies depending on the object of administration,administration route, disease and the like, and when the compound isadministered to an adult as an oral therapeutic agent for Alzheimer'sdisease, the amount of the compound of the present invention as anactive ingredient is about 0.1 to about 20 mg/kg body weight, preferablyabout 0.2 to about 10 mg/kg body weight, more preferably about 0.5 toabout 10 mg/kg body weight, and the agent can be administered in aportion or portions per a day.

Furthermore, the compound may be used in combination with the otheractive ingredients [e.g., choline esterase inhibitors (e.g., Aricept(Donepezil) and the like), cerebral activators (e.g., Vinpocetine andthe like), medicaments for treating Parkinson's disease (e.g., L-Dopa,Deprenyl and the like), medicaments for treating amyotrophic lateralsclerosis (Riluzole and the like), neurotrophic factors and the like].The other active ingredients and the compound of the present inventionor a salt thereof can be used in combination by mixing according to amethod known per se and formulating the mixture in one pharmaceuticalcomposition (e.g., tablet, powder, granule, capsule (including softcapsule), liquid, injection, suppository, sustained-release agent andthe like). The ingredient and the compound may be formulatedindependently, and may be administered to the same object simultaneouslyor at intervals. Alternatively, the compound may be used in combinationwith a drug such as an immunosuppressive agent and the like during orafter implantation of nerve stem cell and pre-nerve cell that have beenprepared from embryonic stem cell and nerve tissue or fetal nervetissue.

The pharmacologically acceptable carrier that may be used in theproduction of the preparation includes various organic or inorganiccarrier substances conventionally used as a preparation material, suchas excipients, lubricating agents, binders, disintegrators for solidpreparations; solvents, dissolution aids, suspending agents, isotonicagents, buffers, soothing agents for liquid preparations, and the like.Furthermore, if necessary, additives such as conventional preservatives,antioxidants, coloring agents, sweetening agents, absorbents, wettingagents and the like can be used.

The excipients include for example lactose, sucrose, D-mannitol, starch,corn starch, crystalline cellulose, light anhydrous silicic acid and thelike.

The lubricating agents include for example magnesium stearate, calciumstearate, talc, colloidal silica and the like.

The binders include for example crystalline cellulose, sucrose,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, saccharose,geratin, methylcellulose, carboxymethylcellulose sodium and the like.

The disintegrators include for example starch, carboxymethylcellulose,carboxymethylcellulose calcium, croscarmelose sodium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.

The solvents include for example water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

The dissolution aids include for example polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate and thelike.

The suspending agents include for example surfactants such astriethanolamine stearate, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride, glycerinemonostearate and the like; hydrophilic polymers such aspolyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like.

The isotonic agents include for example glucose, D-sorbitol, sodiumchloride, glycerine, D-mannitol and the like.

The buffers include for example buffer solutions such as phosphorate,acetate, carbonate, citrate and the like, and the like.

The soothing agents include for example benzylalcohol and the like.

The preservatives include for example paraoxy benzoates, chlorobutanol,benzylalcohol, phenethylalcohol, dehydroacetic acid, sorbic acid and thelike.

The antioxidants include for example sulfite, ascorbic acid,α-tocopherol and the like.

EXAMPLES

Hereinafter the present invention is explained in more detail withreferring to Examples and Reference Examples, which do not limit thepresent invention.

Nuclear magnetic resonance (¹H-NMR) was measured using tetramethylsilaneas an internal standard and using JMTCO400/54 (400 MHz, manufactured byJEOL Co., Ltd.) or R-90H (90 MHz, manufactured by Hitachi Ltd.), and theδ value was represented by ppm. The symbols in the Examples are asfollows.

-   s: singlet, d: doublet, t: triplet, m: multiplet, br: broad,-   J: coupling constant

The excess percentage of enantiomer (% ee) and excess percentage ofdiastereomer (% de) were measured by high performance liquidchromatography using a column for the separation of optical isomers.

-   High performance liquid chromatography condition A-   Column; CHIRALCEL OD (manufactured by Daicel Chemical Industries,    Ltd.)-   Eluent; n-hexane/isopropanol (97/3)-   Flow rate; 0.5 ml/min.-   Detection; UV 230 nm-   Temperature; room temperature-   High performance liquid chromatography condition B-   Column; SUMICHIRAL OA-3300 4.6×250 mm (manufactured by Sumika    Chemical Analysis Service)-   Mobile phase; 0.05 M acetic acid-ammonium-ethanol solution-   Flow rate; 0.3 ml/min-   Detection; UV (254 nm)-   Temperature; room temperature

Example 1 Preparation of(R)-(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

(2S,3S)-(+)-O,O′-Di-(p-toluoyl)tartaric acid (1936 g) was dissolved inisopropylalcohol (14.8 L) at 75° C. A solution of a racemate of2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine(1850 g) in toluene (9244 ml) was then added dropwise thereto and themixture was stirred at the same temperature for 10 min. The mixture wasstirred at 67 to 69° C. for 30 min and cooled to room temperature (25 to30° C.), and the precipitated crystals were collected by filtration,washed with toluene/isopropylalcohol (5:1) to give a diastereomeric salt(2234 g). Melting point 193-194° C., [α]_(D) ²⁵=+79.2° (c=1.0, MeOH)¹H-NMR (DMSO-d₆) δ: 0.88 (3H, s), 1.37 (3H, s), 1.67 (3H,s), 2.01 (3H,s), 2.05 (3H, s), 2.24 (3H, s), 2.39 (6H, s), 4.08 (1H, s), 5.80 (2H,s), 6.60-7.10 (4H, br), 7.27 (4H, d, J=8.0 Hz), 7.89 (4H, d, J=8.0 Hz)

The above-mentioned diastereomeric salt was dissolved in methanol(12.025 L) at 45° C., and 25% aqueous ammonium was added dropwisethereto to adjust the pH to 8.5. The mixture was stirred at 50° C. for10 min. Water (3105 ml) was added thereto, and after the crystals beganto precipitate, additional water (4163 ml) was added thereto. Themixture was stirred at 50° C. for 1 hr, then at 25 to 30° C. for 1 hr,and the crystals were collected by filtration and washed with 50%methanol to give the title compound (805.1 g). Yield 87%.

Melting point 91-92° C., [α]_(D) ²⁵=+5.2° (c=1.0, MeOH)

¹H-NMR (CDCl₃) δ: 1.01 (3H, s), 1.48 (3H, s), 1.79 (3H, s), 2.14 (3H,s), 2.20 (3H, s), 2.31 (3H, s), 3.08 (2H, br), 4.10 (1H, s), 6.60-7.10(4H, br)

Example 2 Preparation of(R)-(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

(2S,3S)-(+)-O,O′-Di-(p-toluoyl)tartaric acid (78.5 g) was dissolved in2-propanol (288 ml). A racemate of2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine(60 g) and acetonitrile (960 ml) were added thereto, and the mixture wasstirred at room temperature for 8 hr. The precipitate was filtered offto give crude crystals. The crystals were suspended in acetonitrile (600ml), stirred overnight under room temperature and filtered. The obtainedcrystals were 54.9 g. Yield 40%. As a result of HPLC analysis, theexcess percentage of the diastereomer was 99% de. Melting point 186-187°C., [α]_(D) ²⁵=+79.9 (c=1.0, MeOH) ¹H-NMR (DMSO-d₆) δ; 0.89 (3H, s),1.37 (3H, s), 1.67 (3H, s), 2.00 (3H, s), 2.05 (3H, s), 2.25 (3H, s),2.40 (6H, s), 4.09 (1H,s), 5.80 (2H, s), 6.60-7.10 (4H, br), 7.39 (4H,d, J=7.8 Hz), 7.89 (4H, d, J=8.0 Hz)

This diastereomeric salt was decomposed in saturated aqueous sodiumhydrogencarbonate (550 ml) and ethyl acetate (550 ml) to give the titlecompound (23.2 g, yield 78%). As a result of HPLC analysis, the excesspercentage of the enantiomer was 99% ee. Melting point 90-91° C.,[α]_(D) ²⁵=+5.1 (c=1.0, MeOH) ¹H-NMR (CDCl₃) δ; 1.00 (3H,s,), 1.46(3H,s), 1.77 (3H,s), 2.12 (3H,s), 2.19 (3H,s), 2.30 (3H,s), 3.23 (1H,br), 4.08 (1H,s), 6.60-7.10 (4H, br)

Example 3 Preparation of(R)-(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

(2S,3S)-(+)-O,O′-Di-(p-toluoyl)tartaric acid (99.3 g) was dissolved in2-propanol (374 ml). A racemate of2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine(80 g) and acetonitrile (1280 ml) were added thereto and the mixture wasstirred at room temperature for 8 hr. The precipitate was filtered offto give crude crystals (97% de). The crystals were suspended inacetonitrile (800 ml) and stirred overnight under room temperature, andthe mixture was filtered. The obtained crystals were 71.7 g. As a resultof HPLC analysis, the excess percentage of the diastereomer was 99% de.

The diastereomeric salt was decomposed in saturated aqueous sodiumhydrogencarbonate (720 ml) and ethyl acetate (720 ml) to give the titlecompound (30.7 g, yield 76%). As a result of HPLC analysis, the excesspercentage of the enantiomer was 99% ee.

Example 4 Preparation of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine

A racemate of 2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine (50 mg) and(S)-(+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine (53.3 mg) were dissolvedin 2-propanol (1 ml) with heating, and the mixture was left in arefrigerator for 20 hr. The precipitated salt was collected byfiltration and washed with 2-propanol (0.3 ml) to give colorlesscrystals (68.1 mg). The crystals were recrystallized from 2-propanol (1ml then 0.6 ml) to give 35.3 mg. (Yield 42.5%) (In the crystals, theresolved substance and the resolution agent were crystallized in theratio of 1:2, and the crystals further contained 1 mol of 2-propanol.)As a result of HPLC analysis, the excess percentage of the diastereomerwas >99.9% de. Melting point 183-185° C. (the crystal form was changedat 120-125° C.), [α]_(D) ²⁵=+50.6° (c=0.52, MeOH) ¹H-NMR (CDCl₃) δ: 0.88(3H, s), 1.03 (3H, s), 1.05 (3H, s), 1.16 (3H, s), 1.18 (3H, s), 1.37(3H, s), 1.65 (3H, s), 1.99 (3H, s), 2.05 (3H, s), 2.83 (1H, m), 3.77(1H, m), 4.07 (1H, s), 4.32 (1H, d, J=4.2 Hz), 5.64 (2H, d, J=7.1 Hz),7.11 (2H, d, J=8.1 Hz), 7.36-7.53 (10H, m), 8.97 (2H, m), 9.13 (4H, d,J=2.2 Hz), 9.87 (2H, d, J=6.8 Hz)

The above-mentioned salt (31 mg) was stirred with aqueous 5% sodiumhydrogencarbonate (1 ml) and ethyl acetate (2 ml) for 10 min. Theorganic layer was separated and concentrated to give the title compoundas a colorless oil (10.4 mg). (Crude yield 47.2%) As a result of HPLCanalysis, the excess percentage of enantiomer of the (+) form havingshort retention time was >99.9% ee.

Example 5 Preparation of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine

A racemate of 2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine (100 mg) and(S)-(+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine (213.2 mg) were dissolvedin 2-propanol (4 ml) with heating, and the solution was left in arefrigerator for 20 hr. The precipitated salt was collected byfiltration and washed with 2-propanol (1 ml) to give colorless crystals(228 mg). The crystals were recrystallized from 2-propanol (4 ml) twiceto give crystals (104 mg, yield 62.6%). (In the crystals, the resolvedsubstance and the resolution agent were crystallized in the ratio of1:2, and the crystals further contained 1 mol of 2-propanol.) As aresult of HPLC analysis, the excess percentage of the diastereomerwas >99.9% de. Melting point 184.5-185.5° C. (the crystal form waschanged at 123-125° C.) Elemental analysis (for C₅₅H₅₉N₇O₁₆) Calcd. forC, 61.50%; H, 5.54%; N, 9.13%; Found. C, 60.63%; H, 5.33%; N, 9.13%.¹H-NMR (CDCl₃) δ: 0.88 (3H, s), 1.03 (3H, s), 1.05 (3H, s), 1.16 (3H,s), 1.18 (3H, s), 1.37 (3H, s), 1.65 (3H, s), 1.99 (3 H, s), 2.05 (3H,s), 2.83 (1H, m), 3.77 (1H, m), 4.07 (1H, s), 4.32 (1H, d, J=4.2 Hz),5.64 (2H, d, J=7.1 Hz), 7.11 (2H, d, J=8.1 Hz), 7.36-7.53 (10H, m), 8.97(2H, m), 9.13 (4H, d, J=2.2 Hz), 9.87 (2H, d, J=6.8 Hz)

The above-mentioned salt (86 mg) was stirred with 5% aqueous sodiumhydrogencarbonate (3 ml) and ethyl acetate (5 ml) for 10 min. Theorganic layer was separated, concentrated and purified by silica gelcolumn chromatography (chloroform/methanol=30/1) to give the titlecompound as a colorless oil (21 mg, yield 50.8%). This oil wascrystallized by leaving it under room temperature. As a result of HPLCanalysis, the excess percentage of the enantiomer for the (+) formhaving short retention time was >99.9% ee. Melting point 75-76° C.,[α]_(D) ²²=+5.2° (c=0.39, MeOH) 1H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.20(3H, s), 1.22 (3H, s), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H, s), 2.19(3H, s), 2.85 (1H, m), 3.24 (2H, bs), 4.08 (1H, s),6.87 (2H, br),7.06-7.08 (2H, m)

Example 6 Preparation of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine

A racemate of2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine(50 mg) and (2S,3S)-(+)-O,O′-di-(p-toluoyl)tartaric acid (59.7 mg) weredissolved in 2-propanol (0.6 ml) and toluene (0.4 ml), and the solutionwas left in a refrigerator for 20 hr. The precipitated crystals werecollected by filtration to give a salt (48.2 mg). The salt wasrecrystallized from 2-propanol (0.4 ml) and toluene (0.25 ml) to givecrystals (32 mg, yield 58.3%). As a result of HPLC analysis, the excesspercentage of diastereomer was >99.9% de. Melting point 185-186° C.¹H-NMR (CDCl₃) δ: 0.89 (3H, s), 1.16 (3H, s), 1.18 (3H, s), 1.38 (3H,s), 1.67 (3H, s), 2.01 (3H, s), 2.05 (3H, s), 2.41 (6H, s), 2.83 (1H,m), 4.09 (1H, s),5.81 (2H, s), 7.12 (2H, d, J=8.1 Hz), 7.40 (4H, d,J=8.1 Hz), 7.89 (4H, d, J=8.3 Hz)

The above-mentioned salt (30 mg) was stirred with 5% aqueous sodiumhydrogencarbonate (1 ml) and ethyl acetate (1 ml) for 10 min. Theorganic layer was separated and concentrated to give the title compoundas a colorless oil (12.3 mg, yield 52.5%). As a result of HPLC analysis,the excess percentage of the enantiomer for the (+) form having shortretention time was >99.9% ee.

Example 7 Preparation of(+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine

A racemate of2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine(50 mg) and(+)-2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane2-oxide (44.9 mg) were dissolved in 2-propanol (0.4 ml) andt-butylmethylether (1 ml), and the solution was left in a refrigeratorfor 20 hr. The precipitated crystals were collected by filtration togive a salt (39.2 mg). This was stirred in 2-propanol (0.4 ml) anddiisopropylether (1 ml) with heating, left at room temperature for 18hr, and filtered. Colorless crystals were obtained (18.5 mg, yield39.0%). As a result of HPLC analysis, the excess percentage of thediastereomer was >99.9% de. Melting point; 220-221° C. ¹H-NMR (CDCl₃) δ:0.61 (3H, s), 0.90 (3H, s), 1.01 (3H, s), 1.16 (3H, s), 1.18 (3H, s),1.38 (3H, s), 1.71 (3H, s), 2.05 (3H, s), 2.07 (3H, s), 2.83 (1H, m),3.84 (1H, dd, J=11.0 Hz, 24.6 Hz), 4.11 (1H, s), 4.42 (1H, d, J=11.0Hz), 6.15 (1H, s), 7.12 (2H, d, J=7.1 Hz), 7.49-7.59 (4H, m), 7.92 (2H,m), 8.26 (1H, d, J=8.8 Hz)

Example 8 Preparation of3-(4-bromophenyl)-2,2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-5-amine

(2S,3S)-(+)-O,O′-Di-(p-toluoyl)tartaric acid (3.86 g) was dissolved inisopropylalcohol (14.2 ml) at 70° C., and a solution of2-(4-bromophenyl)-2,2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-5-amine(3.60 g) in acetonitrile (47.5 ml) was added dropwise thereto whilekeeping the internal temperature at 60° C. The mixture was cooled to 30°C. for about 3 hr, and stirred for 2 hr at the same temperature. Theprecipitated crystals were collected by filtration and washed with asmall amount of cooled acetonitrile. The obtained crude diastereomericsalt was suspended in acetonitrile (29.6 ml) and stirred overnight. Thecrystals were collected by filtration, washed with a small amount ofcooled acetonitrile and dried under reduced pressure. The crystals weresuspended in ethyl acetate (100 ml). Saturated aqueous sodiumhydrogencarbonate (100 ml) was added thereto, and the mixture wasstirred thoroughly and partitioned. The organic layer was washedsuccessively with water (100 ml) and saturated brine (100 ml), and driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was crystallized from cooled hexane togive the title compound (1.13 g, yield 31.4%). As a result of HPLCanalysis, the excess percentage of the enantiomer for the (+) formhaving short retention time was >99.9% ee. Melting point 143-144° C.,[α]_(D) ²⁰=+11.60° (c=0.507, MeOH) ¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.47(3H, s), 1.77 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 3.25 (2H, br), 4.07(1H, s), 6.85 (2H, br), 7.36 (2H, br, J=6.9 Hz).

Reference Example 1 Preparation of ethyl2-methyl-3-(4-methylphenyl)-2-propenoate

To dimethylformamide (1802 ml) that had been cooled to −10° C. was addedsodium tert-butoxide (528.6 g) and the solution was stirred at −5 to 0°C. for 30 min. Triethyl 2-phosphonopropionate (1310 g) was addeddropwise thereto at 10° C. or below. The solution was stirred at 2 to 5°C. for 1 hr, and 4-methylbenzaldehyde (600.8 g) was added dropwisethereto at 10° C. or below and the solution was stirred at roomtemperature for 1 hr. Water was added thereto and the solution wasextracted with toluene. The extract was washed with water and thesolvent was distilled off to give the title compound as an oil (1009 g,yield 98.8%).

¹H-NMR (CDCl₃) δ: 1.35(3H, t, J=7.1 Hz), 2.12(1H, s), 2.37(3H, s),4.27(2H, q, J=7.1 Hz), 7.13-7.32(4H, m), 7.66(1H, s)

Reference Example 2 Preparation of2-methyl-3-(4-methylphenyl)-2-propen-1-ol

To a solution of ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate (1002 g)in toluene (5371 ml) was added dropwise a 70% solution ofdihydrobis(2-methoxyethoxy) sodium aluminate in toluene (2152 g) at 10°C. or below. The solution was stirred at 2 to 5° C. for 1 hr, a 10%solution of Rochel's salt (5968 ml) was added dropwise thereto at 20° C.or below and the solution was stirred at room temperature for 30 min.The toluene layer was fractionated, and washed with a 10% solution ofRochel's salt (2984 ml) and then washed with water. The solvent wasdistilled off to give the title compound as an oil (756 g, yield 93.9%).¹H-NMR (CDCl₃) δ: 1.90(3H, s), 2.34(3H, s), 4.13(2H, s), 6.50(1H, s),7.06-7.20(4H, m)

Reference Example 3 Preparation of1-(3-chloro-2-methyl-1-propenyl)-4-methylbenzene

To a solution of 2-methyl-3-(4-methylphenyl)-2-propen-1-ol (750 g) intoluene (2367 ml) was added dimethylformamide (29.6 ml). To the solutionwas added dropwise thionyl chloride (431.1 ml) at 20° C. or below andthe solution was stirred at 12 to 15° C. for 1.5 hr. Water was thenadded thereto under ice-cooling. The toluene layer was fractionated anda 10% aqueous solution of sodium carbonate was added thereto to adjustthe pH to 5. The toluene layer was fractionated again, washedsuccessively with 5% sodium hydrogencarbonate and 5% brine. The solventwas distilled off to give the title compound as an oil (776.8 g, yield87.3%). ¹H-NMR (CDCl₃) δ: 1.98(3H, s), 2.35(3H, s), 4.21(2H, s),6.55(1H, s), 7.13-7.20(4H, m)

Reference Example 4 Preparation ofN-[2,3,6-trimethyl-4-[[2-methyl-3-(4-methylphenyl)-2-propenyl]oxy]phenyl]formamide

To a mixture of N-(4-hydroxy-2,3,6-trimethylphenyl) formamide (660.4 g),potassium carbonate (1019 g) and dimethylformamide (3302 ml) was added asolution of 1-(3-chloro-2-methyl-1-propenyl)-4-methylbenzene (755 g) intoluene (675 ml), and the mixture was stirred at 50° C. for 14 hr. Water(5944 ml) was then added thereto and the mixture was stirred at 30° C.for 1 hr. The precipitated crystals were collected by filtration andwashed with water and isopropylether to give the title compound (940 g,yield 74.5%). ¹H-NMR (CDCl₃) δ: 1.98(3H, s), 2.07-2.38(9H, m), 2.35(3H,s), 4.53(2H, d, J=6.6 Hz), 6.61(1H, s), 6.82-7.09(1H, m), 7.11-7.31(4H,m), 7.98(0.5H, d, J=12.2 Hz), 8.38(0.5H, s)

Reference Example 5 Preparation ofN-[4-hydroxy-3-[2-methyl-1-(4-methylphenyl)-1-propenyl]-2,5,6-trimethylphenyl]formamide

A mixture ofN-[2,3,6-trimethyl-4-[[2-methyl-3-(4-methylphenyl)-2-propenyl]oxy]phenyl]formamide(920 g), potassium carbonate (4.6 g) and N,N-dimethylaniline (2760 ml)was stirred at 190° C. for 4 hr under nitrogen stream. The mixture wascooled to 100° C. and heptane (1840 ml) was added dropwise thereto. Themixture was further cooled to 30° C. and heptane (3680 ml) was addeddropwise thereto. The mixture was stirred at the same temperature for 1hr, and the precipitated crystals were collected by filtration andwashed with heptane to give the title compound (799.5 g, yield 86.9%).¹NMR (DMSO-d₆) δ: 1.51(3H, s), 1.85(3H, s), 1.89(3H, s), 1.94-2.10(6H,m), 2.24(3H, s), 7.05(4H, s), 7.70(1H, br), 7.77-8.18(1H, m),8.96-9.15(1H, m)

Reference Example 6 Preparation of2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

To a mixture ofN-[4-hydroxy-3-[2-methyl-1-(4-methylphenyl)-1-propenyl]-2,5,6-trimethylphenyl]formamide(740 g) and isobutanol (2220 ml) was added concentrated hydrochloricacid (2220 ml) under nitrogen stream and the mixture was refluxed underheating for 5 hr. The mixture was stirred at 0 to 5° C. for 1 hr. Thecrystals were collected by filtration and washed with toluene to give2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-aminehydrochloride. This hydrochloride was dissolved in a mixed solution ofmethanol (5180 ml)/water (740 ml) at 55 to 60° C. To the solution wasadded dropwise 25% aqueous ammonium at 50° C. to adjust the pH to 8.5,and the mixture was stirred for 30 min. The precipitated crystals werecollected by filtration and washed with methanol/water (1:1) to give thetitle compound (587.2 g, yield 87.4%). ¹H-NMR (CDCl₃) δ: 0.99(3H, s),1.47(3H, s), 1.77(3H, s), 2.12(3H, s), 2.19(3H, s), 2.30(3H, s),3.23(2H, br), 4.08(1H, s), 6.60-7.23(4H, m)

Reference Example 7 Preparation of(R)-(+)-5,6-dimethoxy-2-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)isoindoline

To a solution of 1,2-bischloromethylveratrol (675.9 g) in toluene (4000ml) was added dropwise a solution of(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine(800 g) and N-ethyldiisopropylamine (943.2 g) in toluene (3867 ml) undernitrogen stream, with heating at the inner temperature of 100° C. for4.5 hr. After dropping, the mixture was further stirred at 100° C. for 1hr. The mixture was cooled to the inner temperature of 45° C., methanol(1040 ml) was added thereto and concentrated hydrochloric acid (333.6ml) was added dropwise thereto. After the crystals were precipitated,the mixture was stirred at 50° C. for 30 min and stirred at 5° C. for 1hr. The crystals were collected by filtration, and washed with tolueneand 50% ethanol to give(R)-(+)-5,6-dimethoxy-2-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)isoindoline hydrochloride (1119 g, 83.6%). This hydrochloride wasdissolved in a mixed solution of 90% ethanol (5600 ml) and concentratedhydrochloric acid (110 ml), and 2,6-di-tert-butyl-4-hydroxytoluene (8.0g) was added thereto. To the solution was added dropwise 6.25% aqueousammonium at 50° C. to adjust the pH to 8.0, and water (640 ml) was addedthereto. The mixture was stirred at 50° C. for 30 min and stirred atroom temperature for 1 hr. The precipitated crystals were collected byfiltration, washed with 70% ethanol to give the title compound (935 g,yield 75.5%). Melting point 157-159° C., [α]_(D)=+62.3° (c=0.488, MeOH)¹H-NMR (CDCl₃) δ: 1.01 (3H, s), 1.48 (3H, s), 1.76 (3H, s), 2.17 (3H,s), 2.18 (3H, s), 2.30(3H, s), 3.87 (6H, s), 4.09 (1H, s), 4.45(4H, s),6.76-7.06 (6H, m)

Reference Example 82-Hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide

1) 2,2-Dimethyl-1-(1-naphthyl)-1,3-propanediol

1-Naphthoaldehyde (57.72 g, 0.37 mol) and isobutylaldehyde (55.0 g, 0.76mol) was mixed and 85% potassium hydroxide (24.5 g, 0.37 mol) dissolvedin ethanol (340 ml) was added dropwise thereto with stirring. Exothermicreaction started immediately, and the temperature reached to 65° C. andthen decreased. After dropping for about 15 min, the mixture was stirredat 55° C. for 4.5 hr. The reaction solution was concentrated, and water(300 ml) was added thereto. The mixture was extracted with chloroform(200 ml) twice. The extract was washed with saturated brine, dehydratedwith anhydrous sodium sulfate and concentrated to give the titlecompound as a brown oil (83.62 g, yield 98.1%).

2) 2-Chloro-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide

2,2-Dimethyl-1-(1-naphthyl)-1,3-propanediol (83.6 g, 0.363 mol) andtriethylamine (103.0 g, 1.018 mol) were dissolved in dichloromethane(300 ml). Phosphorus oxychloride (55.4 g, 0.361 mol) dissolved indichloromethane (80 ml) was added dropwise to the solution above undercooling (2 to 4° C.) and with stirring for 1.5 hr. The solution wasstirred at the same temperature for 1 hr, and water (150 ml) was addedthereto to partition. The organic layer was washed with saturated brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. To the obtained dark brown oil was added diethylether (100 ml)and diisopropylether (100 ml) and the mixture was stirred thoroughly andthen ice-cooled for 1 hr. The upper layer containing a large amount ofunreacted 1-naphthoaldehyde was removed by decantation and the underlayer was concentrated to give the title compound as a black tar (76.1g, yield 67.8%).

3) 2-Hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane2-oxide

Sodium hydroxide (29.4 g, 0.735 mol) was dissolved in water (300 ml). Tothe solution was added2-chloro-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide(76.1 g, 0.245 mol) little by little, with stirring and heating at 100°C. The addition was completed for 35 min, and the solution was furtherstirred for 20 min. The reaction solution was cooled to 55° C., whichresulted in precipitation of a large amount of crystals. Under stirring,concentrated hydrochloric acid (73 ml) was added to the mixture toadjust the mixture to acidic, and the mixture solidified and turned intopowder by leaving it for about 1 hr. To the powder was added ether (100ml), and the mixture was stirred and filtered. The obtained crystalswere washed alternately with water and ether and dried to give the titlecompound as pale ocher crystals having the melting point of 216 to 217°C. (41.23 g, yield 57.6%). ¹H-NMR (DMSO-d₆) δ: 0.64 (3H, s), 1.04 (3H,s), 3.94 (1H, dd, J=11.0 Hz, 24.9 Hz), 4.48 (1H, d, J=11.0 Hz), 6.21(1H, s), 7.50-7.64 (4H, m), 7.92-8.01 (2H, m), 8.29 (1H, d, J=13.0 Hz)

4) Optical resolution of(±)-2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane2-oxide

2-Hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide(racemate, 40.0 g, 0.137 mol) and (R)-(−)-(p-hydroxyphenyl) glycine(22.9 g, 0.137 mol) were added to ethanol (600 ml) and water (180 ml)and stirred with heating at 80° C. A small amount of insoluble substancewas filtered off, and the filtrate was left in a refrigerator overnight,and the crystals of the precipitated diastereomeric salt was collectedby filtration. (filtrate A) The crystals were stirred in ethanol withheating, ice-cooled and collected by filtration to give crystals (24.0g). The crystals were suspended in water (170 ml), and 36% hydrochloricacid (23 ml) was added thereto and stirred for 3 hr for decomposition.The crystals were filtered off, washed with water and dried underreduced pressure at 50° C. to give crystals (16.4 g).

The crystals were added to 3.5% hydrochloric acid (250 ml) again andstirred for 1 hr. The crystals were collected by filtration and washedthoroughly with water to give crystals (12.1 g). The obtained crystalswere dissolved in ethanol (500 ml) and decolorized with active carbon.Ethanol (about 300 ml) was then distilled off from the solution, and theresidue was ice-cooled and the precipitated crystals were collected byfiltration to give the (−) form as colorless crystals having the meltingpoint of 207 to 208° C. (8.83 g, yield 44.2%). As a result of the HPLCanalysis (condition B), the excess percentage of the enantiomer was99.6% ee. [α]_(D) ²⁰=−62.0° (c=0.5, MeOH) Elemental analysis (forC₁₅H₁₇O₄P) Calcd. C, 61.64%, H 5.89%; Found. C, 61.58%, H 6.06% ¹H-NMR(DMSO-d₆) δ: 0.64 (3H, s), 1.04 (3H, s), 3.95 (1H, dd, J=11.0 Hz, 24.9Hz), 4.47(1H, d, J=11.0 Hz), 6.21(1H, s), 7.52-7.63(4H, m),7.94-7.98(2H, m), 8.28(1H, d, J=8.0 Hz)

The filtrate A was evaporated to dryness and the residual substance wasstirred in ethanol (150 ml) with heating and ice-cooled, and theprecipitated crystals (4.57 g) were filtered off. The filtrate wasconcentrated and ice-cooled. The further precipitated crystals (1.26 g)were filtered off and the filtrate was concentrated. To the dark brownoil was added water (200 ml) and 36% hydrochloric acid (35 ml) fordecomposition, and the precipitated crystals were filtered off andwashed with water to give crystals containing a large quantity of (+)form (20.79 g). The obtained crystals were dissolved in ethanol (250 ml)with heating. (R)-(+)-1-(1-Naphthyl)ethylamine (12.18 g, 0.071 mol)dissolved in ethanol (50 ml) was added to the above solution and stirredat 80° C. for 2 hr to form hardly soluble crystals of the diastereomericsalt. The solution were left under room temperature for 2 hr and then ina refrigerator overnight, the precipitated crystals were collected byfiltration and washed with ethanol to give crystals (22.47 g). Thefiltrate was concentrated and ice-cooled to give the second crystals(3.14 g) further. These crystals were combined and stirred in ethanol(400 ml) with heating at 80° C. for 45 min and ice-cooled for 4 hr, andthe precipitated crystals were collected by filtration. The obtainedcrystals were heated in ethanol (300 ml), ice-cooled and collected byfiltration to give crystals having the melting point of 250 to 252° C.(decomposed, 16.19 g). [α]_(D) ²⁰=+31.2° (c=0.5, MeOH)

The crystals were suspended in water (120 ml), and concentratedhydrochloric acid (15 ml) was added thereto, and the mixture was stirredfor 4 hr for decomposition. The crystals were collected by filtrationand washed with water. The crystals were stirred again with water (120ml) and 36% hydrochloric acid (15 ml) for 1 hr, filtered and washedthoroughly with water. The crystals were recrystallized from ethanoltwice to give the (+)-form as colorless crystals having the meltingpoint of 205.5 to 206.5° C. (2.24 g, yield 11.2%). As a result of HPLCanalysis (condition B), the excess percentage of the enantiomerwas >99.9% ee. [α]_(D) ²⁰=+62.2° (c=0.5, MeOH)

Reference Example 92-Hydroxy-5,5-dimethyl-4-(2-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide

1) 2,2-Dimethyl-1-(2-naphthyl)-1,3-propanediol

2-Naphthoaldehyde (26.0 g, 0.167 mol) and isobutylaldehyde (24.0 g, 0.33mol) were dissolved in ethanol (50 ml) with heating. 85% Potassiumhydroxide (11.0 g, 0.167 mol) dissolved in ethanol (150 ml) was addeddropwise to the above solution with stirring. Exothermic reactionstarted immediately, and the temperature reached to 51° C. and thendecreased. After the dropping was completed for about 10 min, thesolution was stirred at 55 to 60° C. for 4 hr. The reaction solution wasconcentrated under reduced pressure, and water (150 ml) was addedthereto and the mixture was extracted with chloroform (100 ml) twice.The extract was washed with saturated brine, dehydrated with anhydroussodium sulfate and concentrated to give the title compound as a brownoil (34.86 g, yield 91.0%).

2) 2-Chloro-5,5-dimethyl-4-(2-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide

2,2-Dimethyl-1-(2-naphthyl)-1,3-propanediol (34.86 g, (0.151 mol) andtriethylamine (42.9 g, 0.424 mol) were dissolved in dichloromethane (200ml). Phosphorus oxychloride (24.3 g, 0.158 mol) dissolved indichloromethane (50 ml) was added dropwise to the above solution undercooling to 1 to 4° C. with stirring for 1 hr 40 min. The solution wasstirred at the same temperature for 1 hr, and water (60 ml) was addedthereto to partition the solution. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. To the obtained dark brown oil was added ether(50 ml) and the mixture was stirred thoroughly and left at roomtemperature overnight. The solidified reaction product was pulverized,filtered, washed with ether and dried to give the title compound (38.62g, yield 82.1%). ¹H-NMR (CDCl₃) δ: 0.91(3H, s), 1.14(3H, s),3.87-4.50(2H, m), 5.46(1H, d, J=2.6 Hz), 7.35-7.91(7H, m)

3) 2-Hydroxy-5,5-dimethyl-4-(2-naphthyl)-1,3,2-dioxaphosphorinane2-oxide

Sodium hydroxide (14.9 g, 0.373 mol) was dissolved in water (150 ml). Tothis solution was added little by little2-chloro-5,5-dimethyl-4-(2-naphthyl)-1,3,2-dioxaphosphorinane-2-one(38.6 g, 0.124 mol) with heating to 100 to 102° C. and stirring for 30min. The solution was stirred at the same temperature for 20 min, andthe reaction solution was cooled to 45° C. Concentrated hydrochloricacid (37 ml) was added thereto to adjust the solution to acidic. Thesolution was stirred at 15° C. for 30 min. The crystals were collectedby filtration, washed with water and then ether, and dried under reducedpressure at 60° C. to give the title compound as pale ocher crystalshaving the melting point of 237 to 238° C. (33.87 g, yield 93.2%).¹H-NMR (DMSO-d₆) δ: 0.76(3H, s), 0.95 (3H, s), 3.93(1H, dd, J=11.0 Hz,24.7 Hz), 4.23(1H, d, J=11.0 Hz), 5.43(1H, s), 7.46-7.59(3H, m),7.82-7.98(4H, m)

4) Optical resolution of(±)-2-hydroxy-5,5-dimethyl-4-(2-naphthyl)-1,3,2-dioxaphosphorinane2-oxide

2-Hydroxy-5,5-dimethyl-4-(2-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide(racemate, 31.4 g, 0.107 mol) and (R)-(+)-1-(p-tolyl)ethylamine (14.53g, 0.107 mol) were dissolved in ethanol (350 ml) with heating. Thesolution was stirred at room temperature for 1 hr and under ice-coolingfor 2 hr, and left in a refrigerator overnight to precipitate adiastereomeric salt of the (−) form. This was collected by filtrationand washed with ethanol to give crystals (18.42 g), (the filtrate A). Aserial operation in which the crystals were heated with ethanol, cooledand collected by filtration, was repeated to give crystals having themelting point of 232 to 236° C. (14.54 g). [α]_(D) ²⁰=−43.4° (c=0.5,MeOH)

The crystals were suspended in water (100 ml), and 36% hydrochloric acid(14 ml) was added thereto and stirred for 7 hr for decomposition. Thecrystals were collected by filtration, washed with water, dried underreduced pressure 50° C., and recrystallized from ethanol (2 L) to givethe (−)-form as colorless crystals having the melting point of 210 to211° C. (7.33 g, yield 46.7%). As a result of HPLC analysis (conditionB), the excess percentage of enantiomer was >99.9% ee. [α]_(D) ²⁰=−74.0°(c=0.2, MeOH) Elemental analysis (for C₁₅H₁₇O₄P) Calcd. for C, 61.64%,H, 5.89%; Found. C, 61.58%, H, 5.97% ¹H-NMR (DMSO-d₆) δ: 0.76(3H, s),0.95 (3H, s), 3.94(1H, dd, J=11.0 Hz, 24.7 Hz), 4.23(1H, d, J=11.0 Hz),5.44(1H, s), 7.46-7.56(3H, m), 7.86(1H, s), 7.92-7.98(3H, m)

The filtrate A was evaporated to dryness and the residue was added towater (200 ml) and 36% hydrochloric acid (30 ml), and stirred for 7 hrfor decomposition to give crystals containing a large amount of (+)-form(18.9 g). These crystals were heated with (S)-(−)-1-(p-tolyl)ethylamine(8.7 g, 0.0647 mol) in ethanol (350 ml) at 80° C. for 30 min, and thesolution was stirred for 3 hr under ice-cooling, and the crystals werecollected by filtration. The crystals were added to ethanol (150 ml)again, and the mixture was stirred at 80° C. for 0.5 hr and ice-cooled.The crystals were collected by filtration to give crystals having themelting point of 230 to 232° C. (13.59 g). [α]_(D) ²⁰=+46.4° (c=0.5,MeOH)

The crystals were decomposed with water (100 ml) and 36% hydrochloricacid (13 ml) to give white crystals (9.84 g). These crystals wererecrystallized from methanol (1.8 L), stirred in ethanol (200 ml) at 80°C. for 15 min, ice-cooled and collected by filtration to give the(+)-form as colorless crystals having the melting point of 211 to 212°C. (8.03 g, yield 51.1%). As a result of HPLC analysis (condition B),the excess percentage of enantiomer was >99.9% ee. [α]_(D) ²⁰=+75.5°(c=0.2, MeOH) Elemental analysis (for C₁₅H₁₇O₄P) Calcd. for C, 61.64%,H, 5.89%; Found. C, 61.67%, H, 6.15% ¹H-NMR (DMSO-d₆) δ: 0.76(3H, s),0.95(3H, s), 3.94(1H, dd, J=11.0 Hz, 24.7 Hz), 4.23(1H, d, J=11.0 Hz),5.44(1H, s), 7.46-7.56(3H, m), 7.86 (1H, s), 7.92-7.98(3H, m)

INDUSTRIAL APPLIABILITY

According to the production method of the present invention, a syntheticintermediate for an optically active 2,3-dihydrobenzofuran compound thatis useful itself as a medicine as well as the other medicines forpreventing or treating nerve degenerative diseases and the like can beconveniently and industrially advantageously produced.

1-18. (canceled)
 19. A process for preparing a compound represented bythe formula:

wherein R¹ and R² are each a hydrogen atom or an optionally substitutedhydrocarbon group, R³ is an optionally substituted aromatic group, ringA is an optionally substituted benzene ring, ring B is a 5- to7-membered nitrogen-containing heterocyclic ring optionally substitutedwith a halogen or an optionally substituted hydrocarbon group, ring C isa benzene ring optionally having substituent besides the amino group, ora salt thereof, comprising optically resolving a 2,3-dihydrobenzofurancompound represented by the formula:

wherein the symbols are as defined above, or a salt thereof with anoptically active acidic compound to give a compound represented by theformula:

wherein the symbols are as defined above, or a salt thereof, andreacting the obtained compound (I″) with a compound represented by theformula:

wherein L¹ and L² are each a leaving group and the ring A is as definedabove, or a salt thereof, optionally in the presence of a base.
 20. Theprocess according to claim 19, wherein the ring B is a 5-memberednitrogen-containing heterocyclic ring.
 21. The process according toclaim 19, wherein(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(1-methylethylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindolineor(R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-bromophenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,or a salt thereof is produced.